Title: TGF-BETA SIGNALING IN ENDOMETRIAL CELL FUNCTION AND DYSFUNCTION Project Summary/Abstract An increasing number of reproductive-aged women face pregnancy loss and infertility, some of which is associated with endometrial dysfunction. A lack of understanding of mechanisms governing endometrial development and function prevents an effective treatment for such disorders. Therefore, there is a critical need to define the mechanisms underlying endometrial cell proliferation, differentiation, and function. Research on human endometrial function during pregnancy remains challenging due to ethical constrains on the access to tissue specimens, making the mouse model particularly valuable. Transforming growth factor ? (TGF?) superfamily signaling regulates fundamental cellular functions and developmental processes in reproductive organs including the uterus. The in vivo function of TGF? signaling in uterine biology remains poorly understood due to the redundancy of TGF? ligands and lack of appropriate animal models. By genetically manipulating TGF? type 1 receptor (TGFBR1) using both loss-of-function and gain-of-function mouse models, we have discovered that TGF? signaling is required for fertility and female reproductive tract development. Guided by our compelling preliminary findings, the overall objective in this R01 proposal is to decipher the cellular, molecular, and epigenetic mechanisms underpinning endometrial cell proliferation, differentiation, and function. Our central hypothesis is that endometrial cell properties and function are regulated by a well-balanced TGF? signaling system essential for uterine development and pregnancy. We will test our hypothesis by pursuing the following two specific aims: 1) Define how TGF? signaling regulates endometrial epithelial cell proliferation during uterine development. 2) Identify the role and associated mechanism of TGF? signaling in endometrial stromal cell function and dysfunction during pregnancy. The proposed research is innovative because it involves the use of unique and complementary novel mouse models to decipher the role and associated mechanisms of TGF? signaling in endometrial cells, the application of uterine epithelial and stromal cell culture and co-culture system to uncover how TGF? signaling regulates stromal-epithelial interaction, a key but poorly defined event in uterine development and function, and the identification of TGFBR1-dependent epigenetic mechanisms in endometrial stromal cells. Studies proposed in this application represent the next step in a continuum of research toward the development of targeted interventions for endometrial dysfunction and pregnancy complications. Thus, completion of this proposal is expected to provide a new paradigm for understanding the mechanisms of endometrial dysfunction, and provide a rational basis for future research that focuses on testing the translational potential of targeting TGF? signaling cascade in the treatment of endometrial dysfunction.